All forms of intervention in the arterial circulation may result in intimal hyperplasia (IH)of the involved vessels. These include endarterectomy, balloon dilatation (so-called angioplasty), and bypass grafting procedures, where IH is found to develop in both the graft and at the anastomoses. IH occurs focally or globally, in a significant number of saphenous vein grafts utilized for coronary artery or peripheral artery bypass grafts, where it reaches pathological proportions which result in hemodynamically significant stenosis and occlusion. Surgeons and cardiologists recognize it as an extremely serious problem and there are many who would categorically argue that IH is the number one unsolved problem in the field of vascular surgery. Although IH is a common problem, multiple factors have been associated with its cause and there are no known reliable measures to prevent it or to treat it when it does occur. The working hypothesis of this grant is that with the conversion of a vein (graft) into an arterial conduit, several abrupt changes in wall motion, fluid shear, and oxygen tension occur which alone, or in combination, may functionally alter vascular wall cells and thereby "trigger" the onset of hyperplasia. In this proposal, we will evaluate the functional consequences of these biomechanical and hemodynamic changes, both independently and together, on adult human venous endothelial (EC) and smooth muscle (SMC) cells that have been cultured in a compliant tubular system of our design (Vascular Simulating Device or VSD). In this apparatus, wall motion and fluid shear can be varied independently or in concert. Using the VSD, we will subject EC and SMC to specific levels of mechanical and/or hemodynamic forces which, in vivo, have been correlated with the most intense hyperplastic responses. We will then evaluate the influence of these forces on those cellular functions involved in the development of IH. These include proliferative activity and growth factor production, matrix deposition, and altered thrombotic response. Ultimately we wish to identify the direct cellular targets (eg, transcription factors and promoter elements) that are responsive to specific physical perturbations. Finally, the effects of altered ambient oxygen tension upon IH will be studied. In these experiments, those physical perturbations identified as most critical will be repeated in the VSD under conditions in which a low O2 tension, innate to the venous circulation will be abruptly changed to that of the arterial circulation. The combined experimental results will enable us to identify those biomechanical parameters which induce vein graft hyperplasia. With these factors clearly in focus, we will ultimately be able to develop potential strategies directed against IH.